This invention relates to novel topical analgesic compositions and to their use to alleviate intractable pain.
The treatment of localized intractable pain topically with analgesics historically has not met with significant success, primarily because the surface presented by the affected area, typically skin or mucous membrane, provides an effective barrier to the analgesic agent reaching the situs of the pain. Therefore, physicians must resort to injections to achieve adsorption of the analgesic, which usually also requires that the analgesic agent be in a vehicle which retards the rate of absorption, or to the oral administration of systemic analgesic agents, such as the barbituates. Both of these approaches have obvious limitations and pose well-known problems. There therefore is a long standing need for an effective topical analgesic agent which is effective in ameliorating localized intractable pain and can safely be applied to the situs of the pain by the person in pain.
The compositions of this invention comprise biphenamine (.beta.-diethylaminoethyl 3-phenyl-2-hydroxybenzoate) base or pharmaceutically acceptable acid addition salt thereof. Salts of this compound are known to have a variety of activities, including local anesthetic (U.S. Pat. No. 1,976,922); treatment of seborrhea (U.S. Pat. No. 3,123,531); as well as antihistaminic and bactericidal activity and fungicidal properties (U.S. Pat. No. 2,594,350; Report Annual Meeting So. Med. Assoc., Nov. 6, 1961).
Biphenamine hydrochloride has been sold as a 1% ointment, under the trademark "Melsaphine," as a topical anesthetic agent possessing bactericidal, fungicidal and antihistamine properties and as a 1% aqueous shampoo under the trademark "Alvininex," Federal Register, Vol. 34, No. 189, page 153, Oct. 2, 1969.
Although its use for treating arthritis and related conditions is claimed in U.S. Pat. No. 4,073,897, nothing was known concerning its topical analgesic activity or its usefulness for the treatment of localized intractable pain because the compound is ineffective for ameliorating intractable pain by the topical application thereof, in the absence of a tissue penetrant such as DMSO.
The compositions of this invention also comprise DMSO (dimethyl sulfoxide). U.S. Pat. No. 3,551,554 and 3,711,602 disclose that DMSO is effective as an agent for enhancing tissue penetration of physiologically active agents. U.S. Pat. No. 3,549,770 discloses (Example 36) the topical application of a mixture of acetylsalicylic acid and DMSO is more effective than DMSO alone to relieve the pain and muscle spasm of rheumatoid spondylitis. See also U.S. Pat. No. 3,711,602, 3,711,606 and 3,743,727 and references cited therein. These patents disclose that the tissue penetration of physiologically active compounds, inter alia, steroidal agents and certain antimicrobial agents, can be enhanced with DMSO. U.S. Pat. No. 3,740,420 discloses DMSO compositions for topical administration containing thickening agents.
The foregoing patents disclose that concentrations of DMSO of 10% by weight and above can effect penetration of such agents through various mucous membrane barriers and that concentrations of 50% by weight and above are effective to achieve penetration thereof through the skin. DMSO is also known to enhance the antiperspirant activity astringent of aluminum, zinc and zirconium salts (U.S. Pat. No. 3,499,961).
DMSO has been disclosed as useful for treating a variety of pathological conditions. U.S. Pat. No. 3,549,770 discloses topical application as a particularly advantageous route. This patent claims methods of relieving the signs and symptoms of tissue inflammation; of vascular insufficiency in the blood and lymph circulatory system; of respiratory distress; of arthritis and a method of promoting tissue repair, by administering an effective amount of DMSO, preferably topically. Dosages as low as 0.01 g/kg and up to 1.0 g/kg per day and sometimes higher dosages are contemplated with 0.1-0.2 g/kg individual doses being average. Higher concentrations of DMSO, such as at least 25% and more often at least about 50% are preferred for topical application. Treatment of pain, including "phantom pain," with DMSO preferably by direct application to the involved area is expressly contemplated. In one example (Example 27) the pain associated with skin abrasion was relieved with 15% DMSO in isotonic saline. 10% to 90% water solutions of DMSO, preferably 20% to 40%, in water, alcohol or glycerine are useful for topical application to the mucous membranes of the body although ". . . lower concentrations of DMSO say down to 3% by weight may be useful in some instances."
The use of DMSO as an ataratic agent is disclosed in U.S. Pat. No. 3,790,682. Pharmaceutical compositions containing DMSO and thickening agents are disclosed in U.S. Pat. No. 3,740,420, along with their use to treat and repair damaged tissue, as an antiinflammatory agent, as an analgesic agent, as a muscle relaxant, as an agent for treating vascular insufficiency, and relieve the signs and symptoms of certain specific syndromes, viz., respiratory distress, arthritis and burns. None of the foregoing references disclose or suggest that intractable pain can be treated with low concentrations of DMSO, e.g., topically on the skin at cncentrations below 10%, although U.S. Pat. No. 3,549,770 discloses (Col. 10, lines 42-49) that for pharyngitis or hiccups, the subject may gargle with a more dilute aqueous solution, e.g., containing 1% or preferably 10% by weight of DMSO, and (Col. 28, lines 44-56) that concentrations of DMSO down to 3% by weight may be useful in some instances, with 10% to 90% water solutions being particularly suitable. The effectiveness of DMSO topically for treating pain at concentrations below 10% by weight is not suggested in the prior art. Moreover, I have found that low concentrations of DMSO alone have little if any effect topically upon intractable pain.